The prevalence of Alzheimer's disease (AD) is projected to triple by 2050. To address this imminent public health concern, in 2011 the NIA-AA published revised diagnostic criteria for AD dementia and its anteceding stage, mild cognitive impairment (MCI). These criteria allow providers to determine the likelihood that a patient's cognitive impairment is due to AD using biomarkers of cerebral amyloidosis (e.g. via Amyloid PET) and neurodegeneration (e.g. hippocampal atrophy via structural MRI). Recent tests of these criteria indicate that MCI patients who have biomarker evidence of neurodegeneration are likely to develop dementia, irrespective of amyloidosis. Thus, given the consequential impact of neurodegeneration on dementia onset, the proposed study seeks to address the need for complementary biomarkers of neurodegeneration that can provide specific topographical and neurobiological correlates of cognitive deficits in MCI. The Applicant proposes to develop white matter tract integrity (WMTI) biomarkers of neurodegeneration derived from the biophysical modeling of diffusional kurtosis imaging (DKI) parameters. Study participants will be composed of 80 clinically diagnosed MCI patients who will undergo a clinical evaluation, neuropsychological testing, MRI, and a 2-year follow-up clinical evaluation for diagnostic confirmation. The study aims to determine the extent WMTI metrics of axonal density and myelin integrity detect neurodegeneration throughout the brain beyond hippocampal atrophy, correlate with psychometrically sophisticated tests of memory, language, and executive functions, and complement other investigational MRI biomarkers of neurodegeneration (i.e. cortical atrophy, functional connectivity). The candidate for this Mentored Patient-Oriented Career Development Award (K23), Dr. Benitez, is a clinical neuropsychologist whose career goal is to improve the diagnosis and prognosis of cognitive decline in aging and AD. The proposed K23 will extend her prior training in quantitative MRI of brain white matter compromise in cognitive aging during her institutional KL2 award. Specifically, she proposes didactic and applied training experiences to 1) become proficient in multi-modal MRI research to the level of an independent investigator, 2) acquire foundational knowledge on the neurobiology of aging/AD on which the interpretation of MRI findings is predicated, and 3) develop essential skills in the responsible conduct of clinical research in aging/AD, with the support of an outstanding mentoring team of senior researchers in MRI (Dr. Helpern), aging/AD neurobiology (Dr. Granholm), patient-oriented clinical research (Drs. Clark and Ovbiagele), and biostatistics (Dr. Nietert). By the end of the award, Dr. Benitez will have preliminary data for an R01 that will extend this project to a longitudinal study including Amyloid PET. This R01 will investigate WMTI metrics as clinical biomarkers of both neurodegeneration and amyloidosis, as recent preclinical findings suggest this may be possible with DKI but not diffusion tensor imaging. This work will address a multi-institute funding priority for biomarkers of cognitive decline across neurodegenerative diseases, for which no effective therapies exist.